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ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 136-140

Elevated glycated hemoglobin during pregnancy in diabetic women as a predictor of large-for-gestational age infants in an Asian cohort


1 Department of General Pediatrics and Neonatology, Kandang Kerbau Women's and Children's Hospital; NUS Yong Loo Lin School of Medicine, Nanyang Technological University, Singapore
2 Department of General Pediatrics and Neonatology, Kandang Kerbau Women's and Children's Hospital; NUS Yong Loo Lin School of Medicine, Nanyang Technological University; Department of Neonatology, Kandang Kerbau Women's and Children's Hospital; Duke Nus Medical School; Lee Kong Chian Imperial School of Medicine, Nanyang Technological University, Singapore

Date of Web Publication2-Aug-2018

Correspondence Address:
Dr. R R Pravin
Kandang Kerbau Women's and Children's Hospital, Singapore. NUS Yong Loo Lin School of Medicine
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_13_18

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  Abstract 


Introduction: Diabetes mellitus in pregnancy is often associated with large-for-gestational-age (LGA) infants. However, there is substantial variation in the reported relationship between LGA infants and glycated hemoglobin (HbA1c) values in pregnancies complicated by diabetes mellitus. Our study aims to investigate whether elevated HbA1c values (≥6.5%) during pregnancy are associated with a higher risk of an LGA infant (birth weight ≥90th percentile for gestational age). Methods: A retrospective study was done on a study population of 202 women with diabetes in pregnancy, whose babies were born healthy and at term (37 + 0—41 + 6 weeks) at KK Women's and Children's Hospital, Singapore, between January 1, 2012, and December 31, 2013. Relevant maternal and neonatal data including maternal HbA1c values were extracted from the electronic medical records system. Results: Mothers who had LGA infants had significantly higher HbA1c values as compared against those without (6.8 ± 1.2 vs. 5.8 ± 0.9, P < 0.001). After adjusting for demographics and gestational age, the odds of an LGA infant for women with HbA1c values of ≥6.5% was 8.5 times greater than those with HbA1c <6.5% (odds ratio [OR] 8.5, 95% confidence interval [CI]: 3.6—20.2, P < 0.0001). For each percent increase in HbA1c, the odds of an LGA infant doubled (OR: 2.1, 95% CI: 1.4—3.0, P < 0.0001). Conclusion: Women with HbA1c ≥6.5% during pregnancy have more than eight times the risk of having an LGA infant as compared to women with HbA1c levels <6.5% during pregnancy. Moreover, every 1% increase in HbA1c levels during pregnancy doubled the odds of having an LGA infant.

Keywords: Gestational diabetes, glycated hemoglobin, infants of mothers with gestational diabetes, large for gestational age infants


How to cite this article:
Xin SC, Pravin R R, Rajadurai VS, Chandran S. Elevated glycated hemoglobin during pregnancy in diabetic women as a predictor of large-for-gestational age infants in an Asian cohort. J Clin Neonatol 2018;7:136-40

How to cite this URL:
Xin SC, Pravin R R, Rajadurai VS, Chandran S. Elevated glycated hemoglobin during pregnancy in diabetic women as a predictor of large-for-gestational age infants in an Asian cohort. J Clin Neonatol [serial online] 2018 [cited 2020 Feb 22];7:136-40. Available from: http://www.jcnonweb.com/text.asp?2018/7/3/136/238396



[TAG:2]Introduction[/TAG:2]

The worldwide prevalence of gestational diabetes mellitus (GDM) has increased, most notably in Asian women. This has adverse outcomes on both maternal and fetal health in the long run, placing both mother and child at increased risk of developing diabetes mellitus. Although there are no local studies done on trends of gestational diabetes in local women, studies have shown that women of Asian origin have a higher risk of developing GDM.[1]

Gestational diabetes is diagnosed during pregnancy and resolves 6-week postpartum. The gold standard used in Singapore is a 75 g 2 h oral glucose tolerance test (OGTT). A woman is diagnosed with GDM if her glucose level is above 7.8 mmol/L according to the World Health Organization (WHO) and NICE guidelines.[2] Glycosylated hemoglobin, glycated hemoglobin (HbA1c), is a surrogate measure of glycemic control over 60—80 days and can be used to monitor the maternal control of GDM during her pregnancy.[3]

Pregnancies complicated by GDM result in chronic maternal and fetal hyperglycemic states. This results in hyperplasia of fetal pancreatic β cells, allowing increased secretion of insulin and other growth factors, enhancing the somatic growth of the infant.[4] Hence, gestational diabetes is associated with large-for-gestational-age (LGA) infants. An LGA infant has a birth weight above the 90th percentile when plotted against their gestational age using the Fenton's growth chart. There are short- and long-term complications associated with GDM and LGA infants, namely increased need for a cesarean delivery, intrauterine fetal demise, and increased 5-year risk of developing Type 2 diabetes mellitus.[4] The infant is at a higher risk of immediate mechanical and metabolic complications such as shoulder dystocia, neonatal hypoglycemia, developing metabolic syndrome, diabetes mellitus, and coronary artery disease in the long term.[5]

Studies have been done to correlate HbA1c with neonatal outcomes in Western populations. In a study done by Brans et al. in Texas, no real or relative correlation between maternal HbA1c and neonatal weight was established.[6] A European study led by Damm et al. established that elevated HbA1c, particularly in the third trimester, was associated with a 52% chance of delivering a LGA infant.[7]

However, there is a paucity of data available on the Asian population. The objective of this study was to investigate a correlation between HbA1c values (≥6.5%) during pregnancy and the risk of having an LGA infant (birth weight percentile ≥90th percentile for gestational age).

[TAG:2]Methods[/TAG:2]

This retrospective cohort study was conducted in the Neonatology Department of KK Women's and Children's Hospital, a tertiary perinatal and pediatric center in Singapore. Two hundred and two babies were born to mothers diagnosed with GDM during their current pregnancy from January 1, 2012, to December 31, 2013. Infants of mothers with multiple gestations, congenital anomalies or congenital infections, genetic syndromes, preterm and postterm infants, and other significant maternal medical conditions such as preeclampsia, and incomplete medical records were excluded from this study.

The electronic medical records of infants and mothers were reviewed retrospectively for demographic and clinical information. While OGTTs were done for mothers to diagnose GDM at 28 weeks or earlier as regular screening for mothers with risk factors, HbA1c measurements taken either during the second or third trimester were recorded. HbA1c values were recorded at a median age of 29-week gestation. An elevated maternal HbA1c was ≥6.5% as per the WHO 2011 guidelines.[8]

The birth weight of infants was recorded and plotted against their gestational age using the standard Fenton chart used by the institution. The infants were then classified as LGA if their birth weight was ≥90th percentile per their gestational age.

Relevant demographic, maternal, and infant data were entered into Microsoft Excel. The primary factor of interest was maternal HbA1c and the outcome was if the infant was LGA or non-LGA. Statistical analysis was done using IBM SPSS Version 22 (IBM, United States of America). A logistic regression analysis was performed to determine the correlation between elevated maternal HbA1c and an LGA infant. The logistic regression model was adjusted for maternal and infant demographics, namely, maternal age, race, and infant gestational age and gender. Statistical significance was set at P ≤ 0.05.

This study was approved by the SingHealth Centralized Institutional Review Board: 2014/758/E, Singapore.

[TAG:2]Results[/TAG:2]

Of the 202 mother—infant pairs, 71 (35%) were Malay, 69 (34%) were Chinese, 48 (24%) were Indian, and 14 (7%) were from other races. The mean maternal age was 33.07 (± 4.6 years). Of the neonates, 106 (53.1%) were girls, whereas 96 (46.9%) were boys. Gestational ages at delivery ranged between 37 and 41 weeks (mean 38.3 ± 1.0). Birth weights ranged from 2296 to 5410 g (mean 3330 ± 568). Twenty-one (10.4%) neonates were small for gestational age (SGA), 160 (89.6%) were appropriate for gestational age (AGA), and 21 (10.4%) were LGA. Thirty-seven (18.3%) subjects had an elevated HbA1c measurement above 6.5%, whereas 165 (81.7%) had a normal HbA1c measurement. [Figure 1] shows the distribution of recorded HbA1c values.
Figure 1: Distribution of recorded HbA1c values in mothers with gestational diabetes mellitus

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In the category of mothers with normal HbA1c levels, 15 (9.1%) infants were SGA, 136 (82.4%) were AGA, and 14 (8.5%) were LGA, whereas, in those with elevated HbA1c levels, 6 (16.2%) infants were SGA, 24 (64.9%) were AGA, and 7 (18.9%) were LGA. The proportion of LGA infants in mothers with elevated HbA1c was 10.4% higher than the proportion of LGA infants in mothers with a normal HbA1c value. This is shown in [Table 1] and [Figure 2].
Table 1: Proportion of small for gestational age, appropriate for gestational age, and large-for-gestational age infants in mothers with normal and elevated glycated hemoglobin

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Figure 2: Proportion of small for gestational age, appropriate for gestational age, and large-for-gestational age infants in mothers with normal and elevated HbA1c

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Outcome

With the addition of maternal and gestation age and infant's race and gender into the logistic regression model to adjust for the aforementioned factors, the odds of having an LGA infant for women with HbA1c values ≥6.5% was 8.5 times greater than that for those with HbA1c <6.5% (odds ratio [OR]: 8.5, 95% confidence interval [CI]: 3.6—20.2, P < 0.0001). This is shown in [Table 2].
Table 2: Logistic regression model using elevated glycated hemoglobin versus normal glycated hemoglobin

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The same logistic regression model was repeated and adjusted for the aforementioned four factors. The only variable changed was instead of using elevated versus normal HbA1c; the HbA1c percentage was used as a risk factor for an LGA infant as shown in [Table 3]. For each percent increase in HbA1c, the odds of having an LGA infant doubled (OR: 2.1, 95% CI: 1.4—3.0, P < 0.0001).
Table 3: Logistic regression model using glycated hemoglobin (%)

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[TAG:2]Discussion[/TAG:2]

Universal diabetic screening for GDM facilitates early diagnosis, better control, and hence improves pregnancy outcomes. A local study by Chen et al. also demonstrated that universal screening is a cost-effective intervention for pregnant women as it significantly reduces the complications of GDM by 40%.[9] A study done in Dublin showed that using the WHO 2 h OGTT screening helped to improve inpatient education, optimization of their GDM, and this in turn reduced the need for intervention in delivery and the need for neonatal care facilities.[10] The European multicenter study led by Damm et al. emphasized that glucose levels and HbA1c should be well controlled during the entire pregnancy and not only during a specific trimester to ensure improved outcomes.[7]

While the aforementioned studies are reflective of the Caucasian demographics, our study focused primarily on an Asian demographic in a single center. Our results showed that Asian mothers who had an elevated HbA1c above 6.5% are 8.5 times more likely to have a LGA infant (95% CI: (3.6, 20.2), P < 0.0001) than Asian mothers who had a HbA1c value <6.5%. The logistic regression model allowed for the adjustment of maternal race, age, infant's gender, and gestational age. This statistically significant correlation is important because an elevated HbA1c has negative implications on both the diabetic mother and the infant.

Asians, Africans, Native Americans, and Hispanics have a 5%—8% higher genetic predisposition to GDM compared to the Caucasian population (1.5%—2%). Recurrence of GDM in at-risk ethnic groups is as high as 68%. One-third of mothers will then develop Type 2 diabetes mellitus within 5 years of giving birth.[4] LGA infants also have poorer neonatal outcomes. These macrosomic infants are at a 12.8% higher risk of hypoglycemia, 9.3% higher risk of polycythemia, and 12.6% higher risk of hospital admissions due to hyperbilirubinemia, respiratory distress, and other complications during the 1st week of life.

Our study also objectively concluded that, for every 1% unit increase in HbA1c, the odds of having an LGA infant increased by a factor of 2.1 (95% CI: [1.4, 3.0], P < 0.0001). This is a reminder to ensure that GDM needs to be well controlled from the onset of pregnancy and through all three trimesters to ensure better maternal and fetal outcomes. A study done in Israel highlighted that early control of GDM before 34 weeks resulted in 18% lower rate of LGA infants as compared to late control of GDM after 34 weeks (P < 0.05).[11]

In a study led by Bhavadharini et al. as part of the Women in India with GDM Strategy Project in Tamil Nadu, HbA1c levels were shown to be a predictor of fetal overgrowth. Such studies are extremely relevant in our cultural context due to similar ethnicities in our region and strongly support our conclusion that elevated HbA1c does correlate with a higher risk of LGA babies.[12]

Further research can be done to investigate the relationship of other maternal and neonatal risk factors for having a LGA infant such as an advanced maternal age, maternal obesity, first-degree relative with DM, GDM in a previous pregnancy, preexisting diabetes, a previous macrosomic child, or a previous stillbirth in the Asian population. A recent study by Morrens et al. in Belgium showed that, in women with preexisting Type 1 diabetes, elevated HbA1c in pregnancy and maternal obesity were independent risk factors for large for gestational age infants, emphasizing the need for strict glycemic control during pregnancy to prevent fetal macrosomia.[13]

[TAG:2]Conclusion[/TAG:2]

Elevated HbA1c is a predictor for LGA infants in our local population with every 1% increase in HbA1c doubling the odds of having an LGA infant. The results of this study suggest that it is important to reinforce good glycemic control in Asian women with GDM to decrease their odds of having an LGA infant. It is also important to diagnose and manage GDM early with planned prescreening and follow-up to decrease the complications of having an LGA infant thereby, reducing maternal and perinatal morbidity and mortality.

Acknowledgment

We would like to acknowledge our project statistician, Ms. Gita Krishnaswamy, previously from the Centre for Quantitative Medicine, DUKE-NUS Graduate Medical School, for her contributions to the statistical analysis of our data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care 2007;30 Suppl 2:S141-6.  Back to cited text no. 1
    
2.
Lindsay RS, Catalano PM, Nelson SM. Diagnosis and Treatment of Gestational Diabetes. United Kingdom: Scientific Impact Paper for the Royal College of Obstetricians and Gynaecologists; 2011. Available from: https://www.rcog.org.uk/globalassets/documents/guidelines/sip_no_23.pdf. [Last accessed on 2016 Sep 11].  Back to cited text no. 2
    
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Morris MA, Grandis AS, Litton J. Glycosylated hemoglobin: A sensitive indicator of gestational diabetes. Obstet Gynecol 1986;68:357-61.  Back to cited text no. 3
    
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Hatfield L, Schwoebel A, Lynyak C. Caring for the infant of a diabetic mother. MCN Am J Matern Child Nurs 2011;36:10-6.  Back to cited text no. 4
    
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Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, et al. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 1991;40 Suppl 2:121-5.  Back to cited text no. 5
    
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Brans YW, Huff RW, Shannon DL, Hunter MA. Maternal diabetes and neonatal macrosomia. I. Postpartum maternal hemoglobin A1c levels and neonatal hypoglycemia. Pediatrics 1982;70:576-81.  Back to cited text no. 6
    
7.
Damm P, Mersebach H, Råstam J, Kaaja R, Hod M, McCance DR, et al. Poor pregnancy outcome in women with type 1 diabetes is predicted by elevated HbA1c and spikes of high glucose values in the third trimester. J Matern Fetal Neonatal Med 2014;27:149-54.  Back to cited text no. 7
    
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World Health Organization. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. World Health Organization; 2011. Available from: http://www.who.int/diabetes/publications/report-hba1c_2011.pdf. [Last accessed on 2016 Sep 11].  Back to cited text no. 8
    
9.
Chen PY, Finkelstein EA, Ng MJ, Yap F, Yeo GS, Rajadurai VS, et al. Incremental cost-effectiveness analysis of gestational diabetes mellitus screening strategies in Singapore. Asia Pac J Public Health 2016;28:15-25.  Back to cited text no. 9
    
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Griffin ME, Coffey M, Johnson H, Scanlon P, Foley M, Stronge J, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: Detection rates, gestation at diagnosis and outcome. Diabet Med 2000;17:26-32.  Back to cited text no. 10
    
11.
Shushan A, Ezra Y, Samueloff A. Early treatment of gestational diabetes reduces the rate of fetal macrosomia. Am J Perinatol 1997;14:253-6.  Back to cited text no. 11
    
12.
Bhavadharini B, Mahalakshmi MM, Deepa M, Harish R, Malanda B, Kayal A, et al. Elevated glycated hemoglobin predicts macrosomia among Asian Indian pregnant women (WINGS-9). Indian J Endocrinol Metab 2017;21:184-9.  Back to cited text no. 12
    
13.
Morrens A, Verhaeghe J, Vanhole C, Devlieger R, Mathieu C, Benhalima K, et al. Risk factors for large-for-gestational age infants in pregnant women with type 1 diabetes. BMC Pregnancy Childbirth 2016;16:162.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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